Fluoxetine is a selective serotonin uptake inhibitor presently available for the treatment of depression under the trade name Prozac.TM.. Its chemical name is given as N-methyl-3-phenyl-3-[(.alpha.,.alpha.,.alpha.-trifluoro-p-tolyl)oxy]propyl amine in much of the literature; its name for indexing in Chemical Abstracts is (.+-.)-N-methyl-.gamma.-[4-(trifluoromethyl)phenoxy]benzenepropanamine. Fluoxetine is currently available for therapy as a racemic mixture only. Early reports indicated that there was no advantage to the use of the either pure enantiomer [Robertson et al. J. Med. Chem. 31, 1412-1417 (1988)] of fluoxetine. However, subsequent publications have suggested advantages to the use of the pure S(+) isomer [U.S. Pat. Nos. 5,104,899 and 5,589,511] and the pure R(-) isomer [U.S. Pat. No. 5,648,396]. Thus, processes for the commercial preparation of racemic fluoxetine and of each of its enantiomers are of considerable value. Throughout this application, various references are referred to within parentheses or square brackets. The disclosures of these publications in their entireties are hereby incorporated by reference into this application.
Numerous processes are known in the literature. The original U.S. patents to fluoxetine [U.S. Pat. Nos. 4,314,081 and 4,194,009] describe syntheses beginning from 3-dimethylaminopropiophenone, which is reduced with diborane, chlorinated with thionyl chloride, condensed with 4-trifluoromethylphenol, and demethylated with cyanogen bromide and potassium hydroxide in ethylene glycol. This process was somewhat improved by Robertson et al. [J. Labeled Compound Radiopharm 24, 1397-1404 (1987)] by condensing the alcohol with 4-chlorobenzotrifluoride and by replacing cyanogen bromide with phenylchloroformate.
European application 519842 discloses an improved process in which 3-dimethylamino-1-phenyl-1-propanol is reacted with an alkyl chloroformate and hydrolyzed to provide 3-methylamino-1-phenyl-1-propanol, which is then condensed with 4-chloro- or 4-fluorobenzotrifluoride. European application 457559 describes a chiral synthesis of the 3-dimethylamino-1-phenyl-1-propanol that is used as a starting material in the foregoing European application. The chiral synthesis is accomplished by reduction of the corresponding ketone with lithium aluminum hydride using (2R,3S)-(-)4-dimethylamino-1,2,-diphenyl-3-methyl-2-butanol as a chiral ligand. A similar chiral reduction has been described by Sakuraba et al. [Syn. Lett. 1991, 689-690] using a different chiral reducing agent. Another approach, described in European patent 380924, proceeds by reduction of ethylbenzoylacetate and subsequent aminolysis of the ethyl ester with methylamine. The reduction of ethylbenzoylacetate can also be accomplished in an enantioselective manner using baker's yeast [Kumar et al. Indian J. Chem. 3 1B, 803-809 (1992)]. A ruthenium catalyst having a chiral ligand has been employed in a similar catalytic reduction by Ager and Laneman [Tet. Asymmetry 30, 3327-3355 (1997)].
Numerous other methods have been described for preparing single enantiomers of fluoxetine. These include chiral epoxidation of styrene followed by ring opening with acetone cyanohydrin [Mitchell and Koenig Synthetic Comm. 25, 1231-1238 (1995)]; asymmetric borane reduction of .beta.-chloropropiophenone [Corey et al. Tet. Lett. 30, 5027 (1989)]; and asymmetric epoxidation/reduction [Gao et al. J. Org. Chem. 53, 4081-4085 (1988)].